title: c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer.
abstract: Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Leann S
authors.initials: LS
authors.lastname: Fiore
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Sourik S
authors.initials: SS
authors.lastname: Ganguly
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: James
authors.initials: J
authors.lastname: Sledziona
authors.affiliation: Department of Pathology, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cibull
authors.affiliation: Department of Biostatistics and Markey Cancer Center, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Dana L
authors.initials: DL
authors.lastname: Richards
authors.affiliation: Department of Pathology, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Janna M
authors.initials: JM
authors.lastname: Neltner
authors.affiliation: Department of Biochemistry, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Carol
authors.initials: C
authors.lastname: Beach
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: McCorkle
authors.affiliation: Department of Molecular and Cellular Biology University of Maryland School of Medicine Baltimore, MD 21201.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaetzel
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine Lexington, Kentucky 40536.
authors.forename: Rina
authors.initials: R
authors.lastname: Plattner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002403:Cathepsins / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009374:Neoplasms, Experimental; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D054778:NM23 Nucleoside Diphosphate Kinases; D011743:Pyrimidines; D016315:Proto-Oncogene Proteins c-abl; D002403:Cathepsins; C498826:nilotinib